The objective of this proposal is to study body iron exchange and its regulation. Clinical disorders in iron balance arise from defects in the absorptive process for iron. In nutritional iron deficiency the problem is inadequate supply of available iron from the gastrointestinal lumen, whereas in iron overload there is excessive transfer of iron from the mucosal cell to the circulation. We will examine the interaction between the luminal, mucosal, and systemic phases of iron absorption. Human studies will include the use of a modified extrinsic tag method which measures iron absorption from the total diet. Preliminary results with this technique indicate that food iron availability assumes importance only in iron deficiency. The method will be used to study inhibiting and facilitating diets, dietary conditioning of the mucosal cell, the effect of heme and nonheme iron fortification, and iron absorption in idiopathic hemochromatosis and erythropoietic iron overload. Mucosal handling of iron will be characterized by measuring the concentrations of transferrin and basic and acidic isoferritins in biopsies obtained endoscopically from normals and from patients with iron deficiency and overload. The significance of fecal concentrations of these proteins will be similarly evaluated. Clinical studies of internal regulation will examine the role of the transferrin receptor in iron exchange by relating iron absorption to receptor levels in the intestinal mucosa, gastrointestinal lumen, feces, and circulation. Parallel animal studies will be performed in the rat where greater manipulation of iron and hematopoietic status is possible. A new method for evaluating food iron absorption will be used to study mucosal adaptation. The role of mucosal and excreted iron proteins in iron balance will be evaluated by selectively loading or depleting body iron compartments. Finally, the relationship between iron absorption, transferrin receptor mass in the liver, erythroid, and total body, and receptor levels in the mucosa and gastrointestinal lumen will be determined.